Swainsonine is a substance isolated from Swainsona sp. and locoweed as well as from the fungus Rhizoctonia leguminicola and of the Metarhizium species. It has been reported to be a potent inhibitor of alpha-mannosidase and to block glycoprotein synthesis. Colegate et al., Aust. J. Chem. 32: 2257-2264, 1979. More recently, Swainsonine was reported to counteract the immunosuppresant activity of agents such as the immunosuppressive factor obtained from tumor bearing mice, cyclophosphamide, and mitomycin C. Kino et al., J. Antibiotics, 38(7), 926-935, 1985. Moreover, the ability of Swainsonine to inhibit the metastatic growth of B16 melanoma cells in lungs has been reported. Kino et al., J. Antibiotics, 38(7),936-940, 1985. These results suggest the use of Swainsonine to improve immunresponsiveness where compromised by tumor or infection.
Alpha-mannosidase inhibitors such as Swainsonine are believed to function as immunomodulators and to reduce tumor metastatis by virtue of their ability to interfere with glycoprotein processing, a complex intracellular process in which specific sugars are clipped from a previously more complex oligosaccharide. This interference profoundly affects the resulting glycoprotein of the cell wall, and this, in turn, can affect vital receptors of target cells and of viral membrane as well as the ability of affected cells to bind to other materials. Virus-cell fusion and viral membrane formation can thus be prevented or reduced causing an antiviral effect. In a similar manner, metastasis, which depends on the ability of tumor cells to bind to other tumor cells and to other substances can be interrupted and an antimetastitic effect produced.
.alpha.-Fucosidase, a lysosomal enzyme which catabolizes glycoproteins, is increased considerably in patients with hepatic carcinoma (Deugnier, Y. et al., Hepatology 4: 889-892(1984)). Increased levels of the enzyme, when measured in the serum of these patients, can provide useful diagnostic markers for the disease. Significantly higher levels of .alpha.-fucosidase activities in serum of patients with diabetes mellitus, hepatic cirrhosis and gastric carcinoma have been reported (Reglero, A. et al., Clin. Chem. Acta 103: 155-158, (1980)). When metastatic rat mammary adenocarcinoma cells treated with fucosidase were injected subcutaneously into rats only 20% of them showed metastases as compared to 80% of untreated cells (Wright, L. C. et al., J. Cell Biochem. 37: 49-59,(1988)). .alpha.-L-fucose plays a fundamental role in the process of inhibition of macrophages migration. Thus, increased activities of fucosidase in tumors can be interpreted as a possible mechanism by which cancer cells may directly subvert the process of macrophages activation, thus facilitating xenoplastic growth. Thus, inhibition of .alpha.-fucosidase may provide a useful approach to metastasis.
Applicants have now discovered a new class of alpha-mannosidase and fucosidase inhibitors which are useful as immunomodulators and as antimetastatic agents.